The general aim of this proposal is to carry out DNA linkage studies to identify the gene defects that can cause osteoporosis. The proposal is based on the assumption that the necessary technology is now available to definitively identify and characterize these gene defects with the same experimental strategies that have recently been successful in defining mutated genes causing a number of other diseases. The first part of the project consists of completing DNA linkage studies on seven large families with osteopenia and osteoporosis that we and our collaborators have recently identified and shown to inherit low bone mineral density (BMD) in an apparently monogenic manner. A second part will consist of searching for mutations in one candidate gene (lysyl hydroxylase) for which we have suggestive data for linkage to low BMD in one of the seven families, and a second candidate gene (BMP-2) for which we have suggestive data for linkage to low BMD in another of the seven families. A third part of the project will consist of recruiting additional large families for DNA linkage analyses through our continuing collaboration with Dr. Alan Tenenhouse who sees about 400 new patients per year at his McGilI Bone Centre, and who is currently establishing a network of nine collaborating bone centres through a grant from the Canadian government that will assay BMD and define the bone status in about 9,000 randomly selected adults. A fourth part of the study will extend our collaboration with Dr. Tenenhouse and his colleagues to recruit smaller families that can be used for the newer strategies of affected sib-pair analysis and the affected-pedigree- member method. The data from linkage studies on large families and from the sib-pair and pedigree analyses on smaller families will be used to identify candidate intervals in the genome for genes causing osteopenia and osteoporosis. When the candidate interval contains a gene that is expressed in bone and produces a gene product that is likely to be essential for the normal structure and function of bone, we will analyze the gene for mutations that cause osteopenia and osteoporosis. When the candidate interval is convincingly identified by linkage analyses, but is not known to contain a reasonable candidate gene, we will carry out detailed analyses of the interval to identify the gene or genes at fault.